Therapeutic approaches targeting p53 gain-of-function mutations for esophageal squamous cell carcinoma

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Sasaki Yasushi 札幌医科大学, 医療人育成センター, 教授 (70322328)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: p53 / 機能獲得変異 / p53ファミリー / 食道扁平上皮癌

Outline of Final Research Achievements

TP53 is one of the most thoroughly studied tumor suppressor genes in human cancer. Genetic mutations in TP53 are present in more than 50% of human cancers, leading to dysregulation of its downstream targets. NGS studies have confirmed that TP53 is the most commonly mutated gene in esophageal squamous cell carcinoma (ESCC). Several mutant p53 proteins promote tumor progression through the gain-of-function (GOF) mechanism. In this study, to identify protein coding and non-coding genes regulated by GOF mutant p53, we performed RNA sequencing (RNA-seq), microarray and other functional assays. Our results indicated a p53-mediated transcriptional network involved in various biological functions and tumor suppression.

Free Research Field

がん関連遺伝子

Academic Significance and Societal Importance of the Research Achievements

食道扁平上皮癌では，ほぼ全例でp53変異が検出され，CDKN2A, p63などp53ネットワークに関わる遺伝子の異常に加え，p53ファミリーの腫瘍原性isoformであるΔNp63のコピー数の増加を認めるなど，p53ネットワークの破綻が発症，進展に深く関わっていると考えられる．本研究では，意義が充分解明されていないp53の機能獲得変異を有する腫瘍で変化する転写ネットワークの同定を試みた．この成果は食道扁平上皮癌の有力な分子標的開発につながる基盤研究に発展する可能性がある．